Association of location of BRCA1 and BRCA2 mutations with benefit from olaparib and bevacizumab maintenance in high-grade ovarian cancer : phase III PAOLA-1/ENGOT-ov25 trial subgroup exploratory analysis
Labidi-Galy, S.I. (University of Geneva)
Rodrigues, M. (ARCAGY-GINECO)
Sandoval, J.L. (University of Geneva)
Kurtz, J.E. (ICANS (Institut de Cancérologie Strasbourg Europe))
Heitz, F. (Charité-Universitätsmedizin Berlin)
Mosconi, A.M. (MITO)
Romero, I. (GEICO)
Denison, U. (AGO)
Nagao, S. (Okayama University Hospital)
Vergote, I. (BGOG)
Parma, G. (MANGO)
Nøttrup, T.J. (NSGO)
Rouleau, E. (Cancer Genetics Laboratory)
Garnier, G. (GINECO)
El-Balat, A. (Klinik für Frauenheilkunde und Geburtshilfe)
Zamagni, C. (IRCCS Azienda Ospedaliero-universitaria di Bologna)
Martín-Lorente, Cristina (Institut d'Investigació Biomèdica Sant Pau)
Pujade-Lauraine, Eric (ICANS (Institut de Cancérologie Strasbourg Europe))
Fiévet, A. (Cancer Genetics Laboratory)
Ray-Coquard, I.L. (University Claude Bernard Lyon)
Universitat Autònoma de Barcelona

Data:	2023
Resum:	In the phase III PAOLA-1 study, the addition of maintenance olaparib to bevacizumab in patients with newly diagnosed high-grade ovarian cancer (HGOC) resulted in prolonged progression-free survival (PFS), particularly for homologous recombination deficiency-positive tumors, including those with a BRCA mutation (BRCAm). The magnitude of benefit from olaparib and bevacizumab according to the location of mutation in BRCA1/BRCA2 remains to be explored. Patients with advanced-stage HGOC responding after platinum-based chemotherapy + bevacizumab received maintenance therapy bevacizumab (15 mg/kg q3w for 15 months) + either olaparib (300 mg b. i. d. for 24 months) or placebo. PFS was analyzed in the subgroup of patients with BRCA1m/BRCA2m according to mutation location in the functional domains of BRCA1 [Really Interesting Gene (RING), DNA-binding domain (DBD), or C-terminal domain of BRCA1 (BRCT)] and BRCA2 [RAD51-binding domain (RAD51-BD); DBD]. From 806 randomized patients, 159 harbored BRCA1m (19. 7%) and 74 BRCA2m (9. 2%). BRCA1m in RING, DBD, and BRCT domains was detected in 18, 40, and 33 patients, and BRCA2m in RAD51-BD and DBD in 36 and 13 patients, respectively. After a median follow-up of 25. 5 months, benefit from maintenance olaparib + bevacizumab was observed irrespective of location of BRCAm. The benefit was particularly high for those with BRCA1m located in the DBD, with 24-month PFS estimated to be 89% and 15% [olaparib + bevacizumab versus placebo + bevacizumab hazard ratio = 0. 08 (95% confidence interval 0. 02-0. 28); interaction P = 0. 03]. In BRCA2m patients, 24-month PFS rates for those with mutations located in the DBD were 90% and 100% (olaparib + bevacizumab versus placebo + bevacizumab), respectively. Advanced-stage BRCA-mutated HGOC patients reported PFS benefit from maintenance olaparib and bevacizumab regardless of mutation location. The benefit is particularly high for patients with mutations located in the DBD of BRCA1. Mutations located in the DBD of BRCA2 are also associated with excellent outcome.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	BRCA mutation ; PARP inhibitor ; Genotype ; Location of mutation ; Olaparib ; Ovarian cancer ; Type of mutation
Publicat a:	Annals of oncology, Vol. 34 Núm. 2 (february 2023) , p. 152-162, ISSN 1569-8041

DOI: 10.1016/j.annonc.2022.11.003
PMID: 36564284

11 p, 528.3 KB

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